摘要： 目的 探讨阿尔茨海默病(AD)小鼠模型中经典瞬时受体电位通道3(TRPC3)和血脑屏障(BBB)在β淀粉样蛋白(Aβ)沉积清除中的关系。方法 将60只小鼠随机分为假手术组、模型组、二酰基甘油类似物(OAG)组和吡啶化合物(Pyr3)组,每组15只。侧脑室注射Aβ1-42建立AD小鼠模型。OAG组和Pyr3组小鼠分别连续21 d腹腔注射TRPC3激动剂OAG和抑制剂Pyr3。应用Morris水迷宫实验检测小鼠行为学,伊文思蓝(EB)染色检测小鼠BBB通透性,Western blotting检测小鼠紧密连接蛋白(ZO-1)、Aβ转运受体低密度脂蛋白受体相关蛋白1(LRP-1)表达水平,ELISA测定小鼠海马和血清Aβ1-42浓度。结果 与假手术组比较,模型组小鼠学习记忆能力下降(P<0.001),EB含量增加(P<0.05),ZO-1、LRP-1蛋白表达下降(均P<0.01),脑组织和血清Aβ浓度均升高(P<0.01,P<0.05);与模型组比较,OAG组小鼠的学习记忆能力明显改善(P<0.05),EB含量下降(P<0.05),ZO-1、LRP-1蛋白表达增加(均P<0.05),脑组织Aβ浓度下降(P<0.05),血清Aβ浓度升高(P<0.05)。结论 AD小鼠中,TRPC3可能通过恢复BBB通透性和功能,上调ZO-1和LRP-1蛋白表达,加快脑组织对Aβ沉积的清除,从而改善AD行为学症状。

阿尔茨海默病小鼠模型中TRPC3通过上调ZO-1和LRP-1蛋白表达清除β淀粉样蛋白沉积

张舒蕾, 张丽艳, 李珍慧, 安一鸣, 高翔宇

沈阳医学院基础医学院病理生理学教研室, 沈阳 110034

收稿日期:2021-12-20出版日期:2022-12-30发布日期:2022-12-12
通讯作者:张丽艳E-mail:1580471013@qq.com
作者简介:张舒蕾 (1990-)，女，主治医师，硕士.
基金资助:辽宁省自然科学基金(20170540874)；沈阳医学院科学研究基金(20193101040021)


关键词: 阿尔茨海默病, 经典瞬时受体电位通道3, 低密度脂蛋白受体相关蛋白1, β淀粉样蛋白
Abstract: Objective To investigate the relationship between transient receptor potential canonical 3(TRPC3) and blood-brain barrier (BBB) in the clearance of β-amyloid protein(Aβ) deposition in a mouse model of Alzheimer disease(AD). Methods Sixty mice were randomly divided into sham operation， model，1-oleoyl-2-acetyl-sn-glycerol(OAG)， and ethyl-1-(4-(2，3，3-trichloroacrylamide) phenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (Pyr3) groups(n = 15 per group). The Alzheimer’s disease mouse model was established by injecting Aβ1-42 into the lateral ventricle. Mice in the OAG and Pyr3 groups were injected intraperitoneally with TRPC3 agonist and inhibitor for 21 days. Morris water maze was used to detect the mice’s behavior. Evans blue staining was used to detect the permeability of the BBB. Western blotting was used to detect the expression of zonula occluden-1(ZO-1) and low density lipoprotein receptor-related protein-1(LRP-1). Enzyme-linked immunosorbent assay was used to determine Aβ1-42 concentration in the hippocampus and serum. Results Compared with the sham operation group， the learning and memory ability of the mice decreased in the model group， and the content of Evans blue increased. The expression of ZO-1 and LRP-1 proteins decreased， and the concentration of Aβ in brain tissue and serum increased. Compared with the model group， the learning and memory ability of the mice improved in the OAG group. Evans blue content decreased， and the expression of ZO-1 and LRP-1 proteins increased. The concentration of Aβ decreased in the brain tissue and increased in serum. Conclusion In AD mice， TRPC3 may improve the behavioral symptoms of AD by restoring BBB permeability and function， thereby upregulating the expression of ZO-1 and LRP-1 proteins， and accelerating the clearance of Aβ deposition in brain tissue.
Key words: Alzheimer disease, transient receptor potential canonical 3, low density lipoprotein receptor-related protein-1, β-amyloid protein
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